- Is a 181 gene panel that includes assessment of non-coding variants
Is ideal for patients with a clinical suspicion of syndromic or non-syndromic genetic hearing loss.
Number of genes181
CPT codesSEQ 81430
The Blueprint Genetics Comprehensive Hearing Loss and Deafness Panel (test code EA0501):
Commonly used ICD-10 code(s) when ordering the Comprehensive Hearing Loss and Deafness Panel
|H90.5||Sensorineural hearing loss, unilateral and bilateral|
|Q75.4||Treacher Collins syndrome|
|Q87.89||Branchio-oto-renal (BOR) syndrome|
- Blood (min. 1ml) in an EDTA tube
- Extracted DNA, min. 2 μg in TE buffer or equivalent
- Saliva (Oragene DNA OG-500 kit/OGD-500 or OG-575 & OGD-575)
Label the sample tube with your patient's name, date of birth and the date of sample collection.
Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue. Read more about our sample requirements here.
This comprehensive panel includes genes from the following panels: Alport Syndrome Panel, Branchio-Oto-Renal (BOR) Syndrome Panel, Non-Syndromic Hearing Loss Panel, Pendred Syndrome Panel, Stickler Syndrome Panel, Syndromic Hearing Loss Panel, Usher Syndrome Panel and Waardenburg Syndrome Panel.
Hearing loss is a genetically very heterogenous group of phenotypes varying in severity and causes. Non-syndromic sensorineural hearing loss is a partial or total loss of hearing that occurs without other associated clinical findings. In syndromic hearing loss, symptoms affecting other parts of the body occur in addition to hearing impairment or deafness. Sensorineural hearing loss can be unilateral or bilateral and it can be stable or progressive. In addition, the loss may appear with various intensivity to high, middle or low tones. It is estimated that approximately 60-80% of congenital hearing loss is genetic in origin. Some 60%-to-70% of congenital hereditary hearing impairnment have a non-syndromic origin. The prevalence of non-syndromic hearing loss is 3-4:10,000 neonates and increases with age. In many populations, mutations in GJB2 are the most prevalent explaining up to 50% of all non-syndromic hearing losses. Altogether syndromic hearing loss accounts for 20% to 30% of congenital hearing loss and deafness and the combined prevalence of syndromic hearing loss is approximately 1-2:10,000.
Genes in the Comprehensive Hearing Loss and Deafness Panel and their clinical significance
|ABHD12||Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract||AR||16||20|
|ACTG1*||Deafness, Baraitser-Winter syndrome||AD||27||47|
|ADGRV1||Usher syndrome, Febrile seizures, familial, 4||AR||71||236|
|AIFM1||Deafness, Combined oxidative phosphorylation deficiency 6, Cowchock syndrome||XL||27||31|
|ANKH||Calcium pyrophosphate deposition disease (familial chondrocalcinosis type 2), Craniometaphyseal dysplasia autosomal dominant type||AD||13||20|
|ATP6V1B1||Renal tubular acidosis with deafness||AR||15||56|
|ATP6V1B2||Deafness, congenital, with onychodystrophy, autosomal dominant, Zimmermann-Laband syndrome 2||AD||6||3|
|BCS1L||Bjornstad syndrome, GRACILE syndrome, Leigh syndrome, Mitochondrial complex III deficiency, nuclear type 1||AR||42||37|
|BSND||Sensorineural deafness with mild renal dysfunction, Bartter syndrome||AR||10||20|
|C10ORF2||Perrault syndrome, Mitochondrial DNA depletion syndrome, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 3||AR||37||80|
|CACNA1D||Primary aldosteronism, seizures, and neurologic abnormalities, Sinoatrial node dysfunction and deafness||AD/AR||7||8|
|CD151||Raph blood group, Nephropathy with pretibial epidermolysis bullosa and deafness||AR||1||3|
|CD164||Deafness, autosomal dominant 66||AD||1||1|
|CDC14A||Deafness, autosomal recessive 105||AR||7||9|
|CDH23||Deafness, Usher syndrome||AR/Digenic||94||358|
|CDKN1C||Beckwith-Wiedemann syndrome, IMAGE syndrome||AD||35||81|
|CEP78||Cone rod dystrophy and hearing loss||AR||7||9|
|CHD7||Isolated gonadotropin-releasing hormone deficiency, CHARGE syndrome||AD||276||860|
|CHSY1||Temtamy preaxial brachydactyly syndrome||AR||6||16|
|CIB2||Deafness, Usher syndrome||AR||5||18|
|CLRN1||Retinitis pigmentosa, Usher syndrome||AR||24||39|
|COL11A1||Marshall syndrome, Fibrochondrogenesis, Stickler syndrome type 2||AD/AR||34||94|
|COL11A2||Weissenbacher-Zweymuller syndrome, Deafness, Otospondylomegaepiphyseal dysplasia, Fibrochondrogenesis, Stickler syndrome type 3 (non-ocular)||AD/AR||29||57|
|COL2A1||Avascular necrosis of femoral head, Rhegmatogenous retinal detachment, Epiphyseal dysplasia, with myopia and deafness, Czech dysplasia, Achondrogenesis type 2, Platyspondylic dysplasia Torrance type, Hypochondrogenesis, Spondyloepiphyseal dysplasia congenital (SEDC), Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type, Kniest dysplasia, Spondyloperipheral dysplasia, Mild SED with premature onset arthrosis, SED with metatarsal shortening, Stickler syndrome type 1||AD||180||561|
|COL4A3||Alport syndrome, Hematuria, benign familial||AD/AR||123||264|
|COL4A6||Deafness, with cochlear malformation||XL||11||5|
|COL9A1||Stickler syndrome recessive type, Multiple epiphyseal dysplasia type 6 (EDM6)||AR||9||6|
|COL9A2||Stickler syndrome, Multiple epiphyseal dysplasia type 2 (EDM2)||AD/AR||7||12|
|COL9A3||Multiple epihyseal dysplasia type 3 (EDM3)||AD/AR||10||14|
|DCDC2||Deafness, Nephronophthisis, Sclerosing cholangitis, neonatal||AR||13||9|
|DFNB31||Deafness, Usher syndrome||AR||12||31|
|DIAPH1||Deafness, Seizures, cortical blindness, and microcephaly syndrome (SCBMS)||AD/AR||10||15|
|DIAPH3||Non-syndromic sensorineural deafness||AD||1||9|
|DLX5||Split-hand/foot malformation with sensorineural hearing loss||AR||3||9|
|DNMT1||Neuropathy, hereditary sensory, Cerebellar ataxia, deafness, and narcolepsy||AD||9||20|
|DSPP||Dentin dysplasia, Dentinogenesis imperfecta, Deafness, with dentinogenesis imperfecta||AD||11||53|
|EDN3||Hirschsprung disease, Central hypoventilation syndrome, congenital, Waardenburg syndrome||AD/AR||7||21|
|EDNRB||Hirschsprung disease, ABCD syndrome, Waardenburg syndrome||AD/AR||12||66|
|EPS8L2||Deafness, autosomal recessive 106||AR||2||2|
|EYA1||Otofaciocervical syndrome, Branchiootic syndrome, Branchiootorenal syndrome||AD||56||218|
|EYA4||Dilated cardiomyopathy (DCM), Deafness, autosomal dominant 10||AD||15||28|
|FDXR||Auditory neuropathy and optic atrophy||AR||5||19|
|FGF3||Deafness, congenital with inner ear agenesis, microtia, and microdontia||AR||13||20|
|FGFR3||Lacrimoauriculodentodigital syndrome, Muenke syndrome, Crouzon syndrome with acanthosis nigricans, Camptodactyly, tall stature, and hearing loss (CATSHL) syndrome, Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia type 1, Thanatophoric dysplasia type 2, SADDAN||AD/AR||54||77|
|FOXI1||Pendred syndrome, Enlarged vestibular aqueduct||AR||1||11|
|GJA1*||Oculodentodigital dysplasia mild type, Oculodentodigital dysplasia severe type, Syndactyly type 3||AD/AR||31||107|
|GJB2||Deafness, Bart-Pumphrey syndrome, Keratoderma, palmoplantar, with deafness, Vohwinkel syndrome, Hystrix-like ichthyosis with deafness, Keratitis-icthyosis-deafness syndrome||AD/AR/Digenic||133||405|
|GJB3||Deafness, Erythrokeratodermia variabilis et progressiva 1, Deafness, autosomal dominant 2B||AD/Digenic||11||40|
|GJB6||Deafness, Deafness, autosomal dominant 3B, Ectodermal dysplasia, hidrotic (Clouston syndrome)||AD/AR||10||33|
|GPSM2||Deafness, Chudley-McCullough syndrome||AR||18||11|
|GRHL2||Ectodermal dysplasia/short stature syndrome, Deafness, autosomal dominant 28||AD/AR||12||12|
|HARS*||Usher syndrome, Charcot-Marie-Tooth disease, axonal, type 2W||AR||6||12|
|HOXB1||Facial paresis, hereditary congenital||AR||3||6|
|HSD17B4||Perrault syndrome, D-bifunctional protein deficiency||AR||60||99|
|KCNE1||Long QT syndrome, Jervell and Lange-Nielsen syndrome||AD/AR/Digenic||11||46|
|KCNJ10||Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SESAME syndrome), Pendred syndrome, Enlarged vestibular aqueduct||AR/Digenic||13||29|
|KCNQ1||Short QT syndrome, Long QT syndrome, Atrial fibrillation, Jervell and Lange-Nielsen syndrome||AD/AR/Digenic||298||631|
|KIT||Gastrointestinal stromal tumor, Piebaldism||AD||79||116|
|LARS2||Perrault syndrome, Hydrops, lactic acidosis, and sideroblastic anemia (HLASA)||AR||14||14|
|LRP2||Donnai-Barrow syndrome, Faciooculoacousticorenal syndrome||AR||24||38|
|MAN2B1||Mannosidosis, alpha B, lysosomal||AR||63||149|
|MET||Deafness, Renal cell carcinoma, papillary, Osteofibrous dysplasia, susceptibility to||AD/AR||20||34|
|MITF||Tietz albinism-deafness syndrome, Waardenburg syndrome, Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD)||AD/AR||32||58|
|MYH14||Deafness, Peripheral neuropathy, myopathy, hoarseness, and hearing loss||AD||7||44|
|MYH9||Sebastian syndrome, May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, Macrothrombocytopenia and progressive sensorineural deafness, Deafness, autosomal dominant 17||AD||25||117|
|MYO6||Deafness, Deafness, autosomal dominant, 22||AD/AR||24||68|
|MYO7A||Deafness, Usher syndrome, Deafness, autosomal dominant 11||AD/AR||239||515|
|NARS2||Combined oxidative phosphorylation deficiency||AR||12||12|
|NDP||Exudative vitreoretinopathy, Norrie disease||XL||31||167|
|NLRP3||Neonatal onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome, Chronic infantile neurologic cutaneous articular (CINCA) syndrome, Familial cold-induced autoinflammatory syndrome 1||AD||20||136|
|PAX3||Craniofacial-deafness-hand syndrome, Waardenburg syndrome||AD/AR||54||149|
|PCDH15||Deafness, Usher syndrome||AR/Digenic||113||118|
|PDZD7||Usher syndrome, Deafness, autosomal recessive||AR||11||19|
|PEX1||Heimler syndrome, Peroxisome biogenesis factor disorder 1A, Peroxisome biogenesis factor disorder 1B||AR||112||134|
|PEX26||Adrenoleukodystrophy, neonatal, Zellweger syndrome, Peroxisome biogenesis disorder||AR||13||27|
|PEX6||Heimler syndrome, Peroxisome biogenesis disorder 4A, Peroxisome biogenesis disorder 4B||AR||58||107|
|PNPT1*,#||Deafness, Combined oxidative phosphorylation deficiency, 13||AR||11||13|
|POLR1C||Treacher Collins syndrome||AR||17||21|
|POLR1D||Treacher Collins syndrome||AD/AR||9||26|
|PRPS1*||Phosphoribosylpyrophosphate synthetase I superactivity, Arts syndrome, Charcot-Marie-Tooth disease, X-linked recessive, 5, Deafness, X-linked 1||XL||27||32|
|RMND1*||Combined oxidative phosphorylation deficiency||AR||17||15|
|RPS6KA3||Coffin-Lowry syndrome, Mental retardation||XL||65||171|
|S1PR2||Deafness, autosomal recessive 68||AR||2||3|
|SALL1*||Townes-Brocks syndrome 1||AD||31||87|
|SALL4||Acro-renal-ocular syndrome, Duane-radial ray/Okohiro syndrome||AD||21||56|
|SIX1||Deafness, Branchiootic syndrome, Branchiootorenal syndrome||AD||11||19|
|SLC19A2||Thiamine-responsive megaloblastic anemia syndrome||AR||14||51|
|SLC26A4||Deafness, Pendred syndrome, Enlarged vestibular aqueduct||AR||181||548|
|SLC29A3||Histiocytosis-lymphadenopathy plus syndrome, Dysosteosclerosis||AR||17||25|
|SLC33A1*||Congenital cataracts, hearing loss, and neurodegeneration, Spastic paraplegia 42, autosomal dominant||AD/AR||6||7|
|SLC52A2||Brown-Vialetto-Van Laere syndrome||AR||27||25|
|SLC52A3||Fazio-Londe disease, Brown-Vialetto-Van Laere syndrome||AR||30||42|
|SLITRK6||Deafness and myopia||AR||3||5|
|SMAD4||Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Polyposis, juvenile intestinal, Myhre dysplasia, Hereditary hemorrhagic telangiectasia||AD||179||143|
|SNAI2||Waardenburg syndrome, Piebaldism||AR||2||4|
|SOX10||Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease||AD||56||148|
|SPATA5||Schizophrenia, Epilepsy, hearing loss, and mental retardation syndrome (EHLMRS)||AR||27||27|
|SUCLA2||Mitochondrial DNA depletion syndrome||AR||9||29|
|SUCLG1||Mitochondrial DNA depletion syndrome||AR||12||28|
|TBC1D24||Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome, Deafness, autosomal dominant, 65, Myoclonic epilepsy, infantile, familial, Epileptic encephalopathy, early infantile, 16, Deafness, autosomal recessive 86||AD/AR||43||55|
|TCOF1||Treacher Collins syndrome||AD||50||330|
|TIMM8A*||Mohr-Tranebjaerg syndrome, Jensen syndrome, Opticoacoustic nerve atrophy with dementia||XL||11||21|
|TJP2||Cholestasis, progressive familial intrahepatic, Hypercholanemia, familial, Deafness, autosomal dominant 51||AD/AR||25||27|
|TMC1||Deafness, Deafness, autosomal dominant 36||AD/AR||33||91|
|TRMU||Liver failure, infantile, Reversible infantile respiratory chain deficiency||AR||20||21|
|USH1C||Deafness, Usher syndrome||AR||45||51|
|USH2A||Retinitis pigmentosa 39, Usher syndrome, type 2A||AR||401||1169|
|WBP2||Deafness, autosomal recessive 107||AR||3||3|
|WFS1||Wolfram syndrome, Deafness, Wolfram-like syndrome, autosomal dominant, Deafness, autosomal dominant 6/14/38, Cataract 41||AD/AR||69||362|
* Some, or all, of the gene is duplicated in the genome. Read more.
# The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads).
The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#)
Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Orphanet databases.
Non-coding variants covered by Comprehensive Hearing Loss and Deafness Panel
|Gene||Genomic location HG19||HGVS||RefSeq||RS-number|
- CAP and ISO-15189 accreditations covering all operations at Blueprint Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
- CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
- Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
- Careful construction of clinically effective and scientifically justified gene panels
- Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
- Our publically available analytic validation demonstrating complete details of test performance
- ~1,500 non-coding disease causing variants in Blueprint WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
- Our rigorous variant classification based on modified ACMG variant classification scheme
- Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
- Our comprehensive clinical statements
The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: OTOA (22-27), OTOGL (21), STRC (1-18). Genes with suboptimal coverage in our assay are marked with number sign (#) and genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk (*) if they overlap with the UCSC pseudogene regions. Gene is considered to have suboptimal coverage when >90% of the gene’s target nucleotides are not covered at >20x with mapping quality score (MQ>20) reads. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).
Variants in the KCNE1 gene should not be used for risk assessment at the moment. Specifically, KCNE1 c.253G>A, p.(Asp85Asn) variant has been considered to be a mild risk factor for acquired long QT syndrome. However, in the newest version of the reference genome GRCh38, a gene KCNE1B, nearly identical to KCNE1 has appeared. By using standard NGS technologies, as well as Sanger sequencing, it is not possible to get reliable region-specific sequences for these genes. It is likely that reads that have been earlier mapped to KCNE1 actually belong to KCNE1B. Moreover, it is currently unclear whether KCNE1B produces a protein product, and if a protein is produced, whether the gene is expressed in heart. More independent data characterizing KCNE1B and its function are needed. Currently, all KCNE1 sequence data and the literature related to KCNE1 variants should be interpreted with caution.
- Complex inversions
- Gene conversions
- Balanced translocations
- Mitochondrial DNA variants
- Repeat expansion disorders unless specifically mentioned
- Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).
This test may not reliably detect the following:
- Low level mosaicism (variant with a minor allele fraction of 14.6% is detected with 90% probability)
- Stretches of mononucleotide repeats
- Indels larger than 50bp
- Single exon deletions or duplications
- Variants within pseudogene regions/duplicated segments
The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.
For additional information, please refer to the Test performance section and see our Analytic Validation.
The Blueprint Genetics comprehensive hearing loss and deafness panel covers classical genes associated with Waardenburg syndrome, Alport syndrome, sensorineural hearing loss, unilateral and bilateral, non-syndromic genetic deafness, Pendred syndrome, Usher syndrome, Stickler syndrome, Jervell and Lange-Nielsen syndrome, Mohr-Tranebjaerg syndrome, Norrie disease, Treacher Collins syndrome, CHARGE syndrome and Branchio-oto-renal (BOR) syndrome. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.
Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).
Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient’s phenotype is suggestive of a specific mutation type.
Performance of Blueprint Genetics Whole Exome Sequencing (WES) assay. All individual panels are sliced from WES data.
|Sensitivity % (TP/(TP+FN)||Specificity %|
|Single nucleotide variants||99.65% (412,456/413,893)||>99.99%|
|Insertions, deletions and indels by sequence analysis|
|1-10 bps||96.94% (17,070/17,608)||>99.99%|
|11-50 bps||99.07% (957/966)||>99.99%|
|Copy number variants (exon level dels/dups)|
|Clinical samples (small CNVs, n=52)|
|1 exon level deletion||92.3% (24/26)||NA|
|2 exons level deletion/duplication||100.0% (11/11)||NA|
|3-7 exons level deletion/duplication||93.3% (14/15)||NA|
|Microdeletion/-duplication sdrs (large CNVs, n=37))|
|Size range (0.1-47 Mb)||100% (37/37)|
|Simulated CNV detection|
|2 exons level deletion/duplication||90.98% (7,357/8,086)||99.96%|
|5 exons level deletion/duplication||98.63% (7,975/8,086)||99.98%|
|The performance presented above reached by WES with the following coverage metrics|
|Mean sequencing depth at exome level||174x|
|Nucleotides with >20x sequencing coverage (%)||99.4%|
The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases such as, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.
We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.
Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the Blueprint Genetics Variant Classification Schemes based on the ACMG guideline 2015. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analyzed at our laboratory allowed us to further develop the industry standard.
The final step in the analysis is orthogonal confirmation. Sequence variants classified as pathogenic, likely pathogenic and variants of uncertain significance
(VUS) are confirmed using bi-directional Sanger sequencing when they do not meet our stringent NGS quality metrics for a true positive call.
Reported copy number variations with a size <10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at Blueprint Genetics (Plus analysis only).
Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, congress abstracts and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.
Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counseling.
Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.